PROJECT SUMMARY Defective lens development is a major cause of congenital eye diseases, because the human lens is the culmination of elaborate cell proliferation, differentiation and morphogenesis, requiring precise regulation by signaling pathways. A molecular understanding of lens development could potentially lead to new ways of diagnosing and treating congenital eye diseases originating from defective lens genesis. We have previously demonstrated that Shp2 protein tyrosine phosphatase and Crk adaptor proteins are important for transmitting FGF signaling in lens morphogenesis. In this application, we will investigate the molecular mechanism of Shp2 and Crk functions. Using conditional mutant mice and cell culture models, we will also identify Abl kinases as novel negative regulators of FGF signaling. Furthermore, we will test the hypothesis that FGF signaling, mediated by Crk, regulates the separation of the lens from the surface ectoderm, which underlies the human congenital disease, Peter?s anomaly. As a major signaling pathway, perturbation in FGF signaling can cause not only congenital diseases, but also metabolic syndromes and cancer. Therefore, study of FGF signaling has far reaching implications for both human health and vision research.